Multiple myeloma is a disease characterized by the homing and uncontrolled growth of malignant plasma cells within the confines of the bone marrow. Despite the recent advances in therapy, multiple myeloma remains an incurable disease. 14,000 new cases of multiple myeloma are diagnosed each year in the United States with a five year survival rate of 37%. Although standard therapy will typically cause an initial response, myeloma patients ultimately develop drug resistance and become unresponsive to a variety of anti-cancer agents, a phenomenon known as multidrug resistance (MDR). Clinical observations indicate that despite divergent genetic changes typical of myeloma, current therapy is not curative in any subset of patients. The bone marrow microenvironment presents a rich source of extracellular matrices, cytokines and growth factors produced by constituents residing in the bone marrow stroma, including mesenchymal stem cells, fibroblast and mature osteoblasts, suggesting that the bone marrow microenvironment may contribute to the resistant phenotype and the failure of standard chemotherapy. It has been reported that adhesion of myeloma and leukemia cells to components of the extracellular matrix is sufficient to cause drug resistance. Targeting interactions between the microenvironment and myeloma cells may be an attractive strategy for increasing the efficacy of standard therapy.